Resistance to macrolide antibiotics has increased at alarming rates in recent years, driving the need to develop new and more effective antibiotics. The long term objective of this proposal is to develop a novel 16-membered macrolide antibiotic that is active against erythromycin-resistant Streptococcus pneumoniae and other Gram positive pathogens and which can be produced at reasonable cost. The proposed compound is designed to exhibit its potency through the novel mechanism of synergistic multi-domain ribosomal binding. Consequently, the compound should not induce macrolide resistance and evade all known efflux mechanisms that confer macrolide resistance. Phase I is a proof of principle project to produce a small series of derivatives of a 16- membered macrolide that is a readily available fermentation product, and determine whether the derivatives bind to domain II of the ribosomes and exhibit increased potency against macrolide-resistant strains. Phase II Specific Aims will be to optimize the derivatives to achieve oral bioavailability. Lead compounds will be examined in vitro and in animals for efficacy, toxicity and pharmacokinetics with the intent of advancing one or more to clinical development. PROPOSED COMMERCIAL APPLICATION: Clinical development candidates could be commericialized as anti-infective agents only after approval by the appropriate regulatory authorities.